Cytokine gene expression during the elicitation phase of contact sensitivity: regulation by endogenous IL-4

Recent studies have focused on characterizing the cytokine profile produced in the epidermis during the sensitization phase of contact sensitivity (CS). Some prior studies have also identified altered individual cytokine mRNA profiles in skin or draining lymph nodes (or several cytokine mRNA profiles in the epidermis) during the elicitation phase of CS. In this study we determined the dynamics of appearance of a battery of cytokine mRNA levels in both the epidermis and dermis during the elicitation phase of CS. We isolated mRNA from dispase-separated epidermis and dermis of TNCB-sensitized and naive BALB/c mice at various times after TNCB challenge. Changes in IFN-gamma and IL-4 mRNA levels (by semiquantitative RT-PCR) were more reproducible and dramatic than those of other cytokines studied (IL-1beta, IL-2, IL-10, and IL-12 p40). Compared to naive mice, sensitized mice had significantly elevated IL-4 mRNA signals 9 and 24 h (dermis), and 24 h (epidermis), after TNCB challenge. The increased IL-4 mRNA levels were mast-cell-independent, because sensitized mast-cell-deficient mice showed similar increases in IL-4 mRNA. To examine the role of endogenous IL-4 in CS elicitation, sensitized mice were treated with anti-IL-4 mAb 1 h before challenge. In accord with prior studies, anti-IL-4 mAb-pretreated mice showed increased ear swelling 24 h after challenge compared to mice pretreated with isotype control mAb. Anti-IL-4 mAb pretreatment also enhanced IFN-gamma, IL-2, IL-12 p40, and IL-1beta (but not IL-10) mRNA signals in the dermis of sensitized and challenged mice. These data indicate that IL-4 is produced in murine skin during the elicitation phase of CS and is an important down-modulator of inflammation. IL-4 may blunt CS by regulating local production of proinflammatory cytokines.